Project Summary/Abstract Viral infection has been associated with the development of type 1 diabetes (T1D). Studying virus- associated diabetes in laboratory animals has been problematic due to differences in host species-specific susceptibility and immune responses to viral pathogens including Coxsackie B virus (CVB). In order to better evaluate CVB's impact on causing human T1D, we developed a viral infection model in immunodeficient mice bearing human islet grafts that are crucial for glycemic control. In this model, infection with CVB4 strain JVB leads to diabetes in nearly half of all infected animals. Human islet grafts from infected mice contained viral RNA, expressed viral protein, and exhibited mild to moderate cell degeneration compared to the islet grafts from mock-infected mice. Gene expression profiles from the human grafts revealed induction of interferon- stimulated genes and ER stress, as well as decreased expression of insulin and the transcription factor Pdx1. In the proposed study, we will use this human islet-engrafted mouse model along with complementary studies in cultured human beta cells to delineate the mechanisms of beta cell dysfunction and/or death following CVB infection. We will compare different CVB strains as well as mutant viruses to identify which viruses are more or less diabetogenic. The ultimate goal is to design a preventive vaccine against TID.